Known in the prior art are antisense oligonucleotide techniques making it possible to specifically inhibit a gene in mammal cells. These techniques are based on the introduction into cells a short oligonucleotide of DNA that is complementary to the target gene. This oligonucleotide induces the degradation of the messenger RNA (mRNA) transcribed by the target gene. Another antisense technique comprises introducing into a cell a DNA oligonucleotide which forms a triple strand with the target gene. The formation of this triple strand represses the gene by either blocking access for activating proteins, or in more sophisticated approaches, by inducing degradation of the gene. None of these approaches appear to be based on a cellular mechanism existing in the cells of mammals, and they are not very effective. In fact, the clinical use of antisense has been reduced to a few rare cases, and it was believed that there was no possible use for oligonucleotides forming triple strands.
Interference RNA which is also designated “RNA'inh” or “RNAi” or cosuppression, has been demonstrated in plants. It was observed in plants that the introduction of a long double-strand RNA corresponding to a gene induced the specific and effective repression of the target gene. The mechanism of this interference comprises the degradation of the double-strand RNA into short oligonucleotide duplexes of 20 to 22 nucleotides.
The “RNA'inh” approach, more generally referred to according to the invention as inhibitory oligonucleotides or RNAi, is based on a cellular mechanism whose importance is underlined by its high degree of conservation since this mechanism is conserved throughout the plant and animal kingdoms and species, and has been demonstrated not only in plants but also in the worm Caenorhabditis elegans and yeasts, and mammals—humans and mice.